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Synthetic Metals 163 (2013) 19– 23

Contents lists available at SciVerse ScienceDirect

Synthetic Metals

journa l h o me page: www.elsev ier .com/ locate /synmet

nhanced drug loading capacity of polypyrrole nanowire network for controlledrug release

huhui Jianga, Yanan Suna, Xin Cuia, Xiang Huanga, Yuan Hea, Shan Ji b, Wei Shia, Dongtao Gea,∗

Department of Biomaterials/Biomedical Engineering Research Center, College of Materials, Xiamen University, Xiamen 361005, ChinaSouth African Institute for Advanced Materials Chemistry, University of the Western Cape, Belville 7535, South Africa

r t i c l e i n f o

rticle history:eceived 29 August 2012eceived in revised form 7 December 2012ccepted 11 December 2012vailable online 9 January 2013

eywords:olypyrrole

a b s t r a c t

For a conducting polymer (CP) based drug release system, drug loading is often accomplished by a dopingprocess, in which drug is incorporated into polymer as dopant. Therefore, the drug loading capacity isrelatively low and the range of drugs can be loaded is limited. In the present work, a polypyrrole (PPy)nanowire network is prepared by an electrochemical method and it is found that the micro- and nano-gaps among the individual nanowires of the PPy nanowire network can be used as reservoir to store drugs.Therefore, the drug loading capacity is dependent on the volume of these micro- and nano-vacancies,instead of the doping level. The range of loaded drugs also can be theoretically extended to any drugs,

anowire networkrug release systemonducting polymers

instead of only charged dopants. In fact, it is confirmed here that both hydrophilic and lipophilic drugscan be loaded into the micro- and nano-gaps due to the amphilicity of the PPy nanowire network. As aresult, both drug loading capacity and the range of drugs can be loaded are significantly improved. Afterbeing covered with a protective PPy film, controlled drug release from the prepared system is achievedby electrical stimulation (cyclic voltammetry, CV) and the amount of drug released can be controlled bychanging the scan rate of CV and the thickness of the protective PPy film.

. Introduction

Nanostructured conducting polymers (CPs) have been one ofhe focus research topics in the field of nanoscience for a num-er of years. To date, numerous nanostructures of CPs, such asanowire, nanowire network, nanorod, nanotube, nanoparticle,nd nanobelt have been synthesized and studied [1–4]. Amonghese CP nanostructures, nanowire networks of CPs, for example,olypyrrole (PPy) nanowire network, have attracted a great dealf interest due to their wide applications in the fields of biosen-ors, energy source, and electronics [3,4]. However, there are feweports on the use of PPy nanowire work for controlled drug release.ecently, our group extended the application of PPy nanowire net-ork to this field, obtaining an effective drug release system withigh adenosine triphosphate (ATP) release efficiency [5].

It is well known that CPs can be used as drug carriers due toheir unique doping–dedoping and stimulus–responsive property6–22], where drugs can be incorporated into CPs as dopants and

hen be released upon electrical stimulation. Therefore, the capac-ty of drug loading is dependent on the doping level (which issually low) and the type of drugs is restricted to the charged and

∗ Corresponding author. Tel.: +86 592 2188502; fax: +86 592 2188502.E-mail address: gedt@xmu.edu.cn (D. Ge).

379-6779/$ – see front matter © 2012 Elsevier B.V. All rights reserved.ttp://dx.doi.org/10.1016/j.synthmet.2012.12.010

© 2012 Elsevier B.V. All rights reserved.

small molecules. Actually, relatively low drug loading capacity andlimited range of drugs can be loaded have become two main obsta-cles for the practical applications of the current existing CP-baseddrug release systems.

In the present work, we find that the micro- and nano-gapsamong the individual nanowires of the above mentioned PPynanowire network can be used as reservoir to store drugs. Becausethe space for drug storage has changed from the backbones of theCPs to the vacancies among the nanowires, it is not necessary toconsider the charge and the volume of the loaded drugs. Therefore,both the drug loading capacity and the range of loaded drugs can beimproved significantly. After being covered with a protective PPyfilm for inhibiting drug leakage, controlled drug release from theprepared P–P system (drug-loading PPy nanowire network coatedby a PPy film) is achieved by electrical stimulation (cyclic voltam-metry, CV) and the amount of drug released can be controlled bychanging the scan rate of CV and the thickness of the protective PPyfilm.

2. Experimental

2.1. Chemicals

Pyrrole, para-toluene sulphonic acid sodium salt (p-TS), iron(III) chloride hexahydrate (FeCl3·6H2O), sulfosalicylic acid (SSA)

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nd dimethyl sulfoxide (DMSO) were obtained from Sinopharmhemical Reagent Co., Ltd. (China). Pyrrole was distilled under therotection of nitrogen gas and stored at −20 ◦C. Hexadecane wasot from Aladdin Chemistry Co., Ltd. (China). ATP and dexametha-one (Dex) were purchased from Sangon Biotech Co., Ltd. (China).opamine hydrochloride was bought from Sigma. Hydroxycamp-

othecin (HCPT) and paclitaxel were obtained from Li Shizhenedicine Group Co., Ltd. (China). All other chemicals were of ana-

ytical grade and were used as received. All solutions were preparedsing deionized Milli-Q water (Millipore).

.2. Preparation of drug loaded PPy nanowire network

The PPy nanowire network was synthesized electrochemicallyt room temperature with conventional three-electrode cell byhe use of CHI600D Electrochemical Workstation (Shanghai CHnstruments, China). A bare gold (Au, diameter of 4.0 mm) wassed as working electrode. The counter electrode was a plat-

num wire and a saturated calomel electrode (SCE) was used ashe reference electrode. The electrolyte was an aqueous solutionf 0.145 M pyrrole, 0.085 M p-TS and 0.200 M phosphate bufferolution (pH 7.40). Before the electropolymerization, the elec-rolyte solution was degassed with a nitrogen stream for 5 min.Py nanowire network was grown for 1600 s from the surface of theu electrode at 0.477 mA cm−2. After polymerization, the workinglectrode was removed from the electrolyte and rinsed thoroughlyith de-ionized water, and then dried in air at room tempera-

ure.6.0 �L aqueous solution containing 0.01 M ATP (or 0.01 M SSA,

.02 M Dopamine) or 10 �L DMSO solution containing 0.005 M Dexor 6.0 �L DMSO of 0.01 M HCPT, 5 �L DMSO of 0.01 M Pacitaxel)as then dropped onto the surface of the PPy nanowire network

nd dried in air.

.3. Synthesis of the protective PPy film by chemical vaporeposition (CVD) method

To prevent the stored drugs from leaking, a PPy film was poly-erized on the top of the PPy nanowire network by CVD technique.

he PPy nanowire network-coated Au electrode was mounted in aeaction vessel equipped with a sealing apparatus and a monomernjection port. 10, 15 and 20 �L ethanol solution containing 0.1 MeCl3 were dropped onto PPy nanowire network-coated Au elec-rode, respectively. The reaction chamber was vacuumized at roomemperature until the internal pressure reduced to 10−2 Torr. Then,xcessive pyrrole monomer was injected into the reactor with aicro-syringe. The pyrrole monomers were polymerized on the

urface of the PPy nanowire network at 60 ◦C for 1 h. Subsequently,he obtained P–P system was washed with deionized water foreveral times and dried in air.

.4. Characterization and measurements

The surface morphologies of the PPy nanowire network andhe P–P system were examined by a scanning electron micro-cope (SEM, LEO1530, Germany) operated at 20 kV. The wettability

easurement of the PPy nanowire network was performed on a

RUSS FM 40 MK2 contact angle (CA) goniometer. The static con-act angles were obtained using 3 �L water droplets or hexadecaneroplets. Cyclic voltammetry (CV) test was performed from −0.9o 0.6 V sweeping at a constant scan rate of 0.01 V/s. Fourier trans-orm infrared (FTIR) spectroscopy was recorded on an Avatar 360pectrophotometer (Thermo Nicolet, USA).

Scheme 1. Schematic process of the fabrication and the drug release of the P–Psystem. (a) Electropolymerize PPy nanowire network; (b) add drug; (c) prepare PPyfilm by CVD method; (d) apply electrical stimulation to release drug.

2.5. Drug release

Electrical stimulation of ATP release was carried out in 2 mL NaClsolution (0.9%) stirred with a magnetic stirring bar at room temper-ature, and performed by cycling the potential from −0.9 to +0.6 V atdifferent scan rates. Samples were taken at specific times from therelease medium, analyzed for ATP content by a UV/Vis Spectropho-tometer (UV-1750, Shimadzu, Japan) at 259 nm, and replaced withan equal volume of fresh 0.9% NaCl solution. The spontaneousrelease of ATP was conducted in the same release medium exceptthat the external electrical stimulation was not applied.

Electrical stimulation of Dex release was carried out in 6 mL NaClsolution (0.9%) stirred with a magnetic stirring bar at room temper-ature, and performed by cycling the potential from −0.9 to +0.6 V ata scanning rate of 100 mV/s. Samples were taken at specific timesfrom the release medium, analyzed for Dex content by the sameUV/Vis Spectrophotometer at 242 nm, and replaced with an equalvolume of fresh 0.9% NaCl solution. The spontaneous release of Dexwas conducted in the same release medium except that the externalelectrical stimulation was not applied.

3. Results and discussion

Scheme 1 shows the schematic representation of the synthe-sis and the drug release processes of the P–P system. In the firststep (Scheme 1a), PPy nanowire network was synthesized by asimple one-step electrochemical method. SEM images of the PPynanowire network are shown in Fig. 1. It can be seen clearly thatthe PPy nanowire network exhibits porous interwoven structures,which inspires us to explore whether drugs can be loaded withinthe micro- and nano-gaps of the porous nanowire network.

For this purpose, the surface wettability of the PPy nanowirenetwork was examined. As shown in Fig. 2A, when a dropletof water (3 �L) was deposited on the surface of the nanowirenetwork, the water will penetrate into the vacancies among indi-vidual nanowires and the CA is about 5◦, which indicates asuperhydrophilic behavior. In addition, the lipophilic property ofthe nanowire network was also investigated. It was found thatthe CA of hexadecane on the surface of nanowire network wasabout 18◦ (Fig. 2B), showing excellent lipophilicity. Therefore, theprepared PPy nanowire network shows amphilicity and it is rea-sonable to deduce that both hydrophilic and lipophilic drugs can beloaded into the nanowire network. Here, several drugs, includinghydrophilic drugs such as ATP, SSA, and Dopamine and lipophilicdrugs such as Dex, HCPT and paclitaxel were examined and it wasfound that all of these drugs, either hydrophilic or lipophilic, couldbe loaded easily into the nanowire network. In the following exper-

iments, ATP and Dex were chosen as the model hydrophilic andlipophilic drugs respectively for various tests (Scheme 1b).

To prevent the stored drug from leaking, a protective PPy filmon the surface of the PPy nanowire network should be required.

S. Jiang et al. / Synthetic Metals 163 (2013) 19– 23 21

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nanowire network has clearly redox peaks, which elucidate thatPPy nanowire network has much better electrochemical activitythan the naked Au electrode and thus benefits to subsequent drugrelease.

ig. 1. SEM images of PPy nanowire network: (A) low magnification image; (B) highagnification image.

owever, if the film was prepared in aqueous solution, some of theoaded drug would diffuse to the solution due to the concentrationifference. Therefore, it is difficult to quantify the loaded drug. Toolve this problem, a protective PPy film was polymerized on theurface of the nanowire network by CVD method in our experimentScheme 1c). Because the PPy film was formed in the pyrrole vapornder vacuum and no solution was used, drug leakage was prohib-

ted completely. Fig. 3 shows the morphology of the protective PPylm. It demonstrates that the film has a dense and smooth surfacend the nanostructures were faintly visible.

After covering the nanowire network with the protective film,he whole P–P system with ATP as model hydrophilic drug wereharacterized qualitatively by FTIR spectroscopy in the range of00–4000 cm−1. The results are presented in Fig. 4. The absorp-ion bands at 1568, 1477, 1331 and 1078 cm−1 are attributed to thePy chain. The peak around 1568 cm−1 is associated with the pyr-

ole ring of the combination of C C and C C stretching vibrations.he band at 1477 cm−1 is assigned to the C N stretching vibration.he absorption peaks near 1078 and 1331 cm−1 are attributed tohe deformation vibrations of C H and C N stretching vibrations,

Fig. 2. Water (A) and hexadecane (B) contact angles of PPy nanowire network.

respectively. The presence of ATP in the PPy nanowire network isproved by the appearance of peaks at 1250 cm−1 (correspondingto the P O stretching vibration) and 1085 cm−1 (corresponding tothe P O stretching vibration). The absorption peaks at 2925 and2851 cm−1 were intensified due to the introduction of CH2 and

CH groups in ATP.The electrochemical property of the PPy nanowire network

was evaluated by cyclic voltammetry in 0.9% NaCl aqueous solu-tion (the naked Au electrode was also studied for comparison). Asshown in Fig. 5, the current of naked Au electrode is close to zeroand no obvious redox peaks were observed. In contrast, the PPy

Fig. 3. SEM image of a protective PPy film synthesized by consuming 10 �L oxidantsolution.

22 S. Jiang et al. / Synthetic Metals 163 (2013) 19– 23

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Fig. 6. Percent release of ATP from P–P system (with the protective PPy film synthe-sized by consuming 10 �L oxidant solution) upon CV electrical stimulation from −0.9

that the amount of ATP released decreased with the increase ofthe thickness of the outer protective PPy film. About 91, 66, and44% of ATP were released from the systems with the protective PPy

Fig. 4. FTIR spectra of the P–P system.

After the deposition of the protective PPy film on the PPyanowire network, spontaneous release of ATP from this P–P sys-em at open circuit was investigated (spontaneous release of ATProm PPy nanowire network was also examined for comparison).TP release efficiency was plotted versus time, as shown in Fig. 6.

t is observed that spontaneous ATP release from nanowire net-ork is rather significant. Nearly 99% of loaded ATP was releasedithin 1 h. However, only 18% of ATP was released at open circuitithin 10 h from the P–P system, which indicated that the pres-

nce of the outer protective PPy film could significantly inhibit thepontaneous ATP release.

Then ATP release from the P–P system under CV electrical stim-lation (Scheme 1d) was investigated. As shown in Fig. 6, it wasound that the effect of scan rate of CV on the ATP release efficiencys significant. About 57, 89 and 95% of ATP were released from the–P system at scanning rates of 50, 100, and 200 mV/s within 10 h,

espectively. The results reveal that like the normal CP-based drugelease systems (drugs were loaded by doping), drug release fromhe P–P system also can be performed by electrical stimulation andhe drug release rates can be regulated by changing the CV scan

ig. 5. Cyclic voltammograms of the naked Au electrode and the PPy nanowireetwork at a scanning rate of 10 mV/s in 0.9% NaCl.

to 0.6 V at a scanning rate of 50 mV/s (�), 100 mV/s (�) and 200 mV/s (©), respec-tively, and from PPy nanowire network (�) and P–P system (�) without electricalstimulation.

rates. It is well known that when PPy was switched from the oxi-dized state to the reduced state, it was accompanied by a changein the PPy volume, from its expansion state to the contraction state[22,23]. Therefore, the diminishing of the PPy volume could providethe driving force for the expulsion of ATP. The faster the scan rate,the more frequent the contraction and expansion of the film. As aresult, more drugs were squeezed out.

On the other hand, since the space for the CVD reaction is fixed,if the amount of the pyrrole is excessive and the polymerizationtime is long enough, the thickness of the outer protective PPy filmwill be proportional to the oxidant consumption. In our experiment,three protective PPy films with different thicknesses were preparedby changing the oxidant amounts. As expected, it was observed

Fig. 7. Percent release of ATP upon CV electrical stimulation from −0.9 to 0.6 V ata scanning rate of 100 mV/s from P–P system with the outer protective PPy filmssynthesized by consuming 10 �L (�), 15 �L (�) and 20 �L (�) oxidant solutions,respectively.

S. Jiang et al. / Synthetic Me

Fig. 8. Percent release of Dex upon electrical stimulation from −0.9 to 0.6 V at a scan-nt1

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ing rate of 100 mV/s (�) and spontaneous release (�) from the P–P systems withhe same thickness of the outer protective PPy film that synthesized by consuming0 �L oxidant solution.

lms synthesized by consuming 10, 15, and 20 �L oxidant solu-ions (0.1 M FeCl3) in 12 h, respectively, as shown in Fig. 7. Theseesults revealed that the ATP release efficiency also can be tunedy changing the thickness of the protective PPy film.

In our experiment, release of lipophilic drug Dex from the P–Pystem was also examined. The results present in Fig. 8 show that5% of Dex was released under CV electrical stimulation from −0.9o 0.6 V at a scanning rate of 100 mV/s while only 15% of Dex wasiffused from the system at open circuit, indicating that the releasef lipophilic drug could also be controlled effectively by the presentystem.

. Conclusion

A PPy-based drug release system was developed by depositionf a protective PPy film on the surface of PPy nanowire network.he PPy nanowire network was synthesized by a simple one-steplectrochemical method. It was found that micro- or nano-gapsmong the individual nanowires could be used as reservoirs totore drugs. Interestingly, both hydrophilic and lipophilic drugsould be loaded into the system by taking advantage of amphilicityf the PPy nanowire network and subsequently be released uponlectrical stimulation. The amount of the drug released could be

ontrolled by changing the scan rate of the CV and the thickness ofhe outer protective PPy film. In summary, the drug release systemrepared here not only keeps the advantage of the conventionalPy-based drug release system (drug release can be performed

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by electrical stimulation), but also provides some new merits. Forexample, higher drug loading capacity is achieved and more type ofdrugs can be loaded. Furthermore, other related functional mate-rials such as drug-loading nanoparticles may also be stored withinthe PPy nanowire network and thus offer a new strategy for eas-ily incorporation of drugs or drug carriers. It is expected that thisPPy nanowire network based drug release system may have greatpotential for future clinical applications where high drug loadingcapacity is required.

Acknowledgments

This work was supported by the National Nature ScienceFoundation of China (Nos. 31070845, 31271009, 81271689),the Fundamental Research Funds for the Central Universities(No. 2011121001) and the Natural Science Foundation of FujianProvince (No. 2011J01331).

References

[1] J. Stejskal, I. Sapurina, M. Trchova, Progress in Polymer Science 35 (2010)1420.

[2] D. Li, J.X. Huang, R.B. Kaner, Accounts of Chemical Research 42 (2009) 135.[3] C. Li, H. Bai, G.Q. Shi, Chemical Society Reviews 38 (2009) 2397.[4] H.D. Tran, D. Li, R.B. Kaner, Advanced Materials 21 (2009) 1487.[5] X.N. Ru, W. Shi, X. Huang, X. Cui, B. Ren, D.T. Ge, Electrochimica Acta 56 (2011)

9887.[6] Y. Cho, R.B. Borgens, Langmuir 27 (2011) 6316.[7] D. Svirskis, J. Travas-Sejdic, A. Rodgers, S. Garg, Journal of Controlled Release

146 (2010) 6.[8] D.T. Ge, R.C. Qi, J. Mu, X.N. Ru, S.M. Hong, S. Ji, V. Linkov, W. Shi, Electrochemistry

Communications 12 (2010) 1087.[9] Y.H. Li, R.J. Ewen, S.A. Campbell, J.R. Smith, Journal of Materials Chemistry 22

(2012) 2687.10] C.Y. Wang, P.G. Whitten, C.O. Too, G.G. Wallace, Sensors and Actuators B: Chem-

ical 129 (2008) 605.11] R. Wadhwa, C.F. Lagenaur, X.T. Cui, Journal of Controlled Release 110 (2006)

531.12] D.T. Ge, X.D. Tian, R.C. Qi, S.Q. Huang, J. Mu, S.M. Hong, S.F. Ye, X.M. Zhang, D.H.

Li, W. Shi, Electrochimica Acta 55 (2009) 271.13] S. Geetha, C.R.K. Rao, M. Vijayan, D.C. Trivedi, Analytica Chimica Acta 568 (2006)

119.14] D.T. Ge, X.N. Ru, S.M. Hong, S.H. Jiang, J. Tu, J. Wang, A.F. Zhang, S. Ji, V. Linkov,

B. Ren, W. Shi, Electrochemistry Communications 12 (2010) 1367.15] L. Leprince, A. Dogimont, D. Magnin, S. Demoustier-Champagne, Journal of

Materials Science: Materials in Medicine 21 (2010) 925.16] L.D. Li, C.B. Huang, Journal of the American Society for Mass Spectrometry 18

(2007) 919.17] J.C. Wu, W.M. Mullett, J. Pawliszyn, Analytical Chemistry 74 (2002) 4855.18] G. Bidan, C. Lopez, F. Mendes-Viegas, E. Vieil, A. Gadelle, Biosensors and Bio-

electronics 10 (1995) 219.19] K. Kontturi, P. Pentti, G. Sundholm, Journal of Electroanalytical Chemistry 453

(1998) 231.20] M. Pyo, J.R. Reynolds, Chemistry of Materials 8 (1996) 128.

21] B.C. Thompson, S.E. Moulton, R.T. Richardson, G.G. Wallace, Biomaterials 32

(2011) 3822.22] X.L. Luo, X.T. Cui, Electrochemistry Communications 11 (2009) 402.23] L.M. Lira, S.I. Cordoba de Torresi, Electrochemistry Communications 7 (2005)

717.